Fish collagen peptide GPLGPR as a potent natural DPP-Ⅳ inhibitor against type 2 diabetes

Peptides derived from animal proteins have attracted increasing attention as natural inhibitors of dipeptidyl peptidase-IV(DPP-Ⅳ) for the management of type 2 diabetes mellitus (T2DM). Here, we compared the anti-diabetic potential of fish collagen peptides (FCP), casein peptides (CP), and ovalbumin peptides (OP). Among them, FCP showed the strongest hypoglycemic effect, significantly improving insulin sensitivity and tissue damage in the liver and pancreas of type 2 diabetic mice. LC–MS characterization and molecular docking identified GPLGPR as the most active peptide within FCP. GPLGPR bound tightly to the DPP-Ⅳ catalytic pocket through hydrogen bonding with Glu205 and Glu206 and hydrophobic interactions with Phe357, Tyr547, and Trp629, consistent with a competitive inhibition mode. In vivo, GPLGPR suppressed DPP-Ⅳ activity, elevated serum GLP-1 levels, and reduced hepatic gluconeogenic gene expression, thereby improving glucose metabolism and alleviating diabetic symptoms such as weight loss, polydipsia, and tissue injury. Collectively, these findings identify GPLGPR as a potent natural DPP-Ⅳ inhibitory peptide with strong potential for dietary intervention in T2DM.